Efficacy and safety of orlistat in male patients with overweight/obesity and hyperuricemia: results of a randomized, double-blind, placebo-controlled trial

Background Obesity is associated with elevated serum uric acid (SUA) levels and frequent gout flares. Losing weight can reduce the SUA level and gout flares. The effect of orlistat on SUA levels and gout flares in patients with overweight/obesity and hyperuricemia (HUA) has not been extensively studied. This study investigated the effects of orlistat on SUA levels and gout flares compared to placebo in overweight and obese patients with HUA. Methods A total of 72 Chinese patients with overweight/obesity and HUA were randomly divided into a placebo group (35, 48.6%) and an orlistat group (37, 51.4%); the trial lasted 12 weeks. The primary endpoints were the relative changes in body weight, the SUA level, and gout flares in the per-protocol population. Results Orlistat reduced the proportion of patients with gout flares (log-rank P = 0.023, hazard ratio = 0.31, 95% confidence interval 0.11–0.85). There was no significant difference in SUA level between the two groups. The average weight loss of the orlistat group was 2.85 kg, and the average weight loss of the placebo group was 0.76 kg. The weight loss in the orlistat group was significantly greater than that in the control group (P < 0.05). Conclusions This study is the first to demonstrate that orlistat has no significant effect on SUA levels in patients with overweight/obesity and HUA. The utility of orlistat as an adjunct therapy to prevent gout flares during weight loss in patients with HUA was emphasized. Trial registration Clinicaltrials.gov NCT05496075. Supplementary Information The online version contains supplementary material available at 10.1186/s12944-024-02047-7.

effect of the orlistat group was signi cantly better than that of the control group (P < 0.05).
Conclusions : This study is the rst to demonstrate that orlistat has no signi cant effect on SUA levels in patients with overweight/obese and HUA.The value of orlistat as an adjunct therapy to prevent gout ares during weight loss in patients with HUA was emphasized.
Trial registration: Clinicaltrials.govNCT05496075 Keywords: hyperuricemia; orlistat; uric acid; gout are Introduction Hyperuricemia (HUA) is a metabolic disease caused by abnormal purine metabolism and /or reduced excretion of uric acid in the body.The prevalence of HUA in China is 13.3% at present, and shows a trend of younger people.With the development of society and change of lifestyle, the prevalence of HUA will further increase (1).Elevated serum uric acid (SUA) may be deposited in articular and non-articular structures to form monosodium uric acid crystals, leading to gout ares(2), manifested by sudden onset of joint pain, erythema, fever, swelling, and dysfunction(3).In addition, HUA is closely associated with metabolic syndrome, type 2 diabetes, hypertension, cardiovascular disease, chronic kidney disease, and is an independent risk factor for premature mortality (4)(5)(6).HUA is considered to be a multifactorial chronic disease related to genetic, environmental and metabolic factors(7).It is particularly emphasized that excess body weight as a major risk factor for the high prevalence of HUA.Epidemiological studies have shown that for every 4 unit increase in body mass index (BMI), SUA can increase by 250μmol/L, and the risk of HUA increases by 7.49 times (8).Animal study has found that obesity promotes increased uric acid production through the hypoxia mechanism of adipocytes(9).The long-term effects of weight loss can help to lower uric acid and relieve gout ares by reducing obesity(10).Given these ndings, weight loss is warranted for patients with overweight/obese and HUA.Orlistat is a potent and irreversible inhibitor of lipase that blocks the absorption of triglycerides from the diet(11).Orlistat has been approved by China National Medical Products Administration for the treatment of obese patients.In clinical trials, orlistat has been shown to be effective in improving obesity and related diseases such as metabolic fatty liver disease(12, 13).However, the effect of orlistat on SUA in obese patients remains controversial.In obese patients with metabolic fatty liver disease, there was no signi cant difference in the change of SUA between the orlistat group and the control group (13,14).Orlistat combined with Diane-35 signi cantly reduced SUA in overweight and obese patients with polycystic ovary syndrome, but there was no signi cant difference compared with Diane-35 alone(15).Orlistat combined with a low-calorie diet (HCD) signi cantly improved SUA in patients with type 2 diabetes compared to HCD alone(16).In summary, there is no conclusive evidence for the effect of orlistat on SUA.
Studies of orlistat in SUA and gout ares in people with overweight/obese and HUA have not been reported and further research is needed.The primary objective of this study was to prospectively evaluate the exact effect of orlistat on uratelowering and gout ares in patients with overweight/obesity and HUA to inform clinicians' treatment choices.Patients and Methods Study design This study as a randomized, double-blind, placebo-controlled trial.and orlistat groups received 120 mg of placebo and orlistat three times a day within one hour after meals, respectively.
Patients in both groups were instructed to maintain their diet, exercise, and rest habits for nearly six months.The allocation of subjects and their intervention strategies are blinded to both the investigator and the subject.Follow-up All participants had a medical history taken at enrollment, including history of HUA, lifestyle habits (smoking, alcohol and drinking sweetened beverages), comorbidities and family history.Subjects underwent face-to-face visits at clinic at weeks 0, 4, 8, and 12 for anthropometric parameter measurements (height, weight, waist circumference and blood pressure) and biochemical tests including glucose, uric acid, lipid levels, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamate transpeptidase (γ-GT), creatinine, urea, and estimated glomerular ltration rate (eGFR).EGFR was calculated using the CKD-EPI equation.All laboratory measurements were performed using standard methodologies.In addition, at each visit, the occurrence of adverse events including oil spots and gout ares was asked and assessed.If the participants had a gout are during follow-up, 0.5-1.5mgcolchicine was given over 24 hours depending on the severity of the are, or additional treatment is provided at the discretion of the investigator.At baseline, all patients had joint ultrasound assessments of the knee, ankle, metatarsophalangeal joints and their associated tendons, and the semi-quantitative OMERACT scoring system was used to assess double contour signs (DC), tophus (larger crystal deposits) and aggregation (smaller crystal deposits).At weeks 0 and 12, controlled attenuation parameter (CAP) and liver stifness measurement (LSM) were performed by a trained operator using FibroScan 502 (Echosens, Paris, France) to assess changes in liver fat content and degree of liver brosis.IOI-353 (Yuseong, South Korea) was used to measure the changes in body fat composition.Statistical analysis The sample size calculations were based on the success rate of orlistat (65.0%) in reducing liver fat content compared to the control group (17.9%) (13).A sample of 56 participants (approximately 28 in each group) provided a power of 95% (with a 2-sided alpha level of <0.05), and allowed up to 20% of the dropout rate to maintain acceptable power (>80%).
The Kolmogorov-Smirnov test was used to check the distribution of parameters.Continuous variables with normal and non-normal distributions are expressed as mean ± standard deviation and median (quartile ), respectively.Categorical variables are expressed as frequency (percentage).
The mean of the normally distributed parameters was compared using the unpaired two-sided Student's t test.In other cases, the Mann-Whitney U test was used for comparison between groups.

Categorical variables were analysed using Chi-square tests or Fisher precision tests
. Bilateral P values < 0.05 was considered statistically signi cant.To compare the risk of gout ares between the two groups after initiating orlistat or placebo treatment, the investigator recorded the number of gout ares per month.
For the rst gout are analysis, follow-up ended at the rst of the following events: the occurrence of the rst gout are or the end of the study.A Cox proportional hazard model was used to estimate the hazard ratio (HR) of the rst gout are and its 95%CI during follow-up.The difference between the two groups was compared by log-rank test.The intention-to-treat analysis population includes all participants who have received at least one treatment with orlistat or placebo as the primary analysis population for baseline demographic and clinical characteristic analysis.The perprotocol population only includes participants who adhere to the study protocol without any primary protocol deviation and serves as the primary and secondary endpoint analysis population.All statistical analyses were performed using SAS 9.4.Results Baseline characteristics Of the 72 enrolled participants with overweight/obese and HUA, 37 were randomly assigned to the orlistat group and 35 to the placebo group (Figure 1). 2 (5.41%) and 7 (20.00%)patients in the orlistat and placebo groups withdraw from the study, respectively, leaving 63 subjects for the per-protocol analysis.The most common reasons for discontinuation of treatment are loss of follow-up and withdrawal of consent.At baseline, the results of demography, biochemical test, FibroScan and joint ultrasound results were balanced in both groups.There was no signi cant difference between the two groups in history of HUA and lifestyle habits (Table 1).The average BMI of patients in the orlistat group was 30.33 and that of patients in the placebo group was 29.22.The mean baseline SUA of patients in the orlistat group was 9.53 versus 9.51 in the placebo group.The mean duration of HUA was 5.5 years in the orlistat group and 6. 0 years in the placebo group .There were 26 (74.29%) and 29 (78.38%)patients with gout in the two groups, respectively (Table 1).Effect on gout ares The proportion of patients with gout in the two groups was comparable in the total population and in patients who completed follow-up, ranging from 74.29% to 78.38%.The average duration of gout ranged from 5.0 to 6.0 years, the average frequency of gout ares in the year prior to enrollment was 1 episode/year, and the mean score of tophus was between 1.13 and 1.17 (Table 1, Table 2).During the study period, orlistat was associated with a lower percentage of patients with gout ares (log-rank P = 0.023, HR = 0.31, 95% CI 0.11-0.85; Figure 2a) in total participants and a lower percentage of patients with recurrent gout ares in participants with gout (log-rank P = 0.012, HR = 0.27, 95% CI 0.10-0.75; Figure 2b).Gout ares were reported and recorded by the investigator.Gout ares are mostly mild or moderate in severity.A total of 11 (39.29%) in the control group had gout ares, compared with 5 (14.28%) in the orlistat group.The proportion of patients with gout ares per month in the total population over time is shown in Figure 2c.All of those gout ares occurred in patients with gout, and the proportion of patients with recurrent gout ares per month in the participants with gout is shown in Figure 2d.Changes in SUA level During the study period, there was no signi cant change in SUA in either the orlistat group or the placebo group.There was no difference in the pattern of SUA change between the two groups (P time >0.05,P group*time >0.05) whether in total participants (Figure 3a) or in participants with gout (Figure 3b).Among all participants, the changes in SUA levels in the orlistat group at 4, 8, and 12 weeks after treatment were -0.26, 0.16, and -0.10mg/dl, respectively.The placebo group was 0.11, 0.12, and 0.23mg/dl, respectively.
There was no signi cant difference in changes in SUA levels between the two groups (Figure 3c).In participants with gout, there was also no signi cant difference in changes in SUA levels between the two groups (Figure 3d).Changes in obesity and metabolic markers During the follow-up period, anthropometric indicators showed a downward trend in orlistat group (Tables 2 and Figure 4).Among these measures, patients in the orlistat group showed greater improvement in body weight, BMI, waist circumference, and body fat content at week 12 compared with those in the placebo group (Figure 4).In addition, the orlistat group also showed signi cant improvements in lipid metabolism, liver fat content and liver brosis.Absolute changes in biological measures, including liver function, kidney function and glucose metabolism, did not differ over time (Table 2).Safety Adverse events and the patient's mental and physical condition were recorded by investigator at each visit.In the orlistat group, 10 (27.03%) participants experienced oil spots, 4 (10.81%)participants experienced mild diarrhea, and 2 (5.41%) participants experienced tolerable loss of appetite and abdominal distension. 2 (5.41%) participants dropped out due to the negative impact of steatorrhea on work and life.No other adverse events were reported in the placebo group except for gout ares (Table S1).Discussion This randomized, double-blind, placebo-controlled study shows that orlistat reduces the rate of gout recurrence in patients with gout.Orlistat was associated with a lower percentage of patients with gout ares (log-rank P = 0.023, HR = 0.31, 95% CI 0.11-0.85) in total participants.In contrast, neither group showed a signi cant advantage in lowering SUA.
As expected, Orlistat group was better than placebo group in improving anthropometric indicators such as body weight, waist circumference, body fat content, lipid metabolism, liver fat content and liver brosis.In the study, patients with overweight/obese and HUA treated with orlistat lost an average of 2.85kg of body weight over a 3-month period, which was signi cantly higher than that of the control group.This is consistent with previous ndings (12, 13).Obesity has been shown to be associated with increased ares of gout(18) , while weight loss can reduce the frequency of gout ares(19).For example, gout patients who lost 7.7 kg of weight through diet management reduced the frequency of gout ares from 2.1 to 0.6 per month(20).Gout patients who underwent bariatric surgery also had signi cantly lower rates of gout ares one year after surgery (21).In this study, the proportion of patients with gout was similar between the two groups, and the duration of gout, the frequency of gout ares in the year prior to enrollment, and the joint ultrasound signs were all comparable at baseline.However, during the 12-week follow-up, the rate of gout recurrence was signi cantly lower in the orlistat group than in the control group.This may be because the weight-loss effect of orlistat reduces the frequency of gout ares.In addition, there was a signi cant decrease in LDL in the orlistat group, which may also account for the lower rate of gout ares.Because previous studies have shown that high LDL is associated with frequent ares of gout(22).In addition, gout ares are often induced in obese patients in the early stage of weight loss (21,23).Recurrent gout ares often cause patients to lose con dence in the current treatment, make it di cult to adhere to the treatment, and are not conducive to long-term weight loss.But this phenomenon was not seen in the study.This may be due to orlistat downregulating in ammatory response in the body, which suppresses gout ares.There are currently no known direct studies on the effect of orlistat on gout ares.But orlistat has been shown to reduce the body's in ammatory response.In obese rats, orlistat not only has a favorable effect on antioxidant enzymes, but also reduces lipid peroxidation levels, thus alleviating oxidative stress.Moreover, it can inhibit nuclear factor kappa-B, which mediates in ammation, and improve endothelial dysfunction(24).In Polycystic ovarian syndrome (PCOS) rats, orlistat can restore the disturbed metabolism of linoleic acid, arachidonic acid, galactose and glycerol, and thus attenuate the chronic in ammation in PCOS rats (25).Orlistat has been shown to inhibit the progression of myocardial damage in obese rats by attenuating oxidative stress, inhibiting the NF-κβ pathway, and caspase-dependent apoptosis (26).Moreover, in obese mice with severe acute pancreatitis, orlistat alleviates adipose tissue necrosis by inhibiting the NLRP3-caspase1 in ammasome pathway of adipose tissue macrophages(27).Activation of the NLRP3 in ammasome also plays a crucial role in the acute symptoms of gout, which leading to the release of IL-1β and other pro-in ammatory cytokines (28).Therefore, Orlistat is likely to reduce the in ammatory response in obese gout patients, thereby suppressing gout ares.The inhibition of gout ares by orlistat during weight loss could be an adjunctive treatment option for obese gout patients to help reduce gout ares induced in the early stages of weight loss.Weight loss is thought to be directly related to urate-lowering.Therapeutic lifestyle changes and bariatric surgery have both been shown to signi cantly lower SUA(29).But the effect of orlistat on SUA has been an unresolved and controversial issue in patients with HUA.The results showed that patients treated with orlistat had an average reduction in SUA levels of 0.10 mg/dl after losing 2.85 kg of weight at 3 months, which is consistent with the dose-response relationship of changes in SUA levels with body weight in other studies(10).The study demonstrates for the rst time that orlistat has no signi cant urate-lowering effect in patients with overweight/obese and HUA.This may be due to the limited weight loss of orlistat, which is not enough to lower SUA.Orlistat inhibits only about 30% of dietary fat absorption.In 1 year, only 2 -5 kg of weight can be lost (30), which is far from the goal of achieving a healthy weight for large weight people.
Addressed The study has several advantages.First, this study prospectively identi ed for the rst time that orlistat has no direct effect on SUA in overweight/obese patients with HUA.Second, this study provide evidence for the potential of orlistat as an adjuvant therapy for the early stages of weight loss.There are several limitations to the study.First, the study period was not long enough to capture the effects of orlistat on weight loss, uric acid-lowering, and gout ares over a longer study period.Second, this study included only male patients with HUA and were unable to compare the combined effect of orlistat between male and female patients while excluding gender differences in the results.
Conclusions In summary, this randomized, double-blind, placebo-controlled study demonstrated for the rst time that orlistat has no signi cant effect on SUA levels in patients with overweight/obese and HUA.In addition, this study found that orlistat was associated with a lower rate of recurrent gout are during weight loss, suggesting that orlistat may be used as an adjunctive therapy in the early stage of weight loss.Further studies are needed to clarify the mechanism of orlistat on preventing gout are.